Cotton rats previously immunized with a chimeric FG glycoprotein of human respiratory syncytial virus (RSV) developed enhanced pulmonary histopathology following challenge with RSV. This potentiation of pathology was not observed in animals previously immunized with an adenovirus-F or vaccinia-F recombinant. Unlike RSV infection or infection by an adenovirus-F or vaccinia virus-F recombinant which each induced a moderate to high level of serum RSV neutralizing antibodies, immunization with RSV FG induced a low titer of serum RSV neutralizing antibodies although the total quantity of antibodies produced was very high. As a consequence, FG immunized cotton rats were not resistant to RSV challenge. These abundant "low quality" antibodies do not appear to be responsible for enhanced pulmonary pathology during subsequent RSV infection because passive transfer of post-immunization sera to other animals did not result in enhancement of lung lesions during RSV infection. This suggests that enhanced histopathology is mediated by RSV-specific T-cells. Enhanced pulmonary histopathology was also observed in mice previously immunized with formalin-inactivated (FI) vaccine. FI RSV-immunized mice depleted of CD4 T-cells prior to RSV challenge, but not those depleted of CD8 T-cells, failed to develop enhanced pulmonary histopathology indicating that CD4 T-cells were the mediators of enhanced pulmonary histopathology. During a study in which mice were immunized with one of a series of vaccinia-RSV recombinant viruses that separately encode a single RSV protein, it was observed that the F, G, N, and M2 proteins each induced resistance to RSV challenge, but the resistance induced by N and M2 was relatively short-lived. This study suggested that RSV vaccines need only contain F and G glycoproteins, because the other RSV proteins either fail to induce resistance or induce immunity that is less effective and more transient than the resistance provided by the F and G antigens. The resistance induced by M2 was shown to be mediated by CD8 T-cells.